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Krawiec ME, Westcott JY, Chu HW, et al. Persistent wheezingin very young children is associated with lower respiratory in-flammation. Am J Respir Crit Care Med 2001;163:1338-43.

Bisgaard H, Hermansen MN, Buchvald F, et al. Childhoodasthma after bacterial colonization of the airway in neonates.N Engl J Med 2007;357:1487-95.

Schaub B, Campo M, He H, et al. Neonatal immune respons-es to TLR2 stimulation: influence of maternal atopy on Foxp3and IL-10 expression. Respir Res 2006;7:40.

Holt PG, Upham JW, Sly PD. Contemporaneous maturation ofimmunologic and respiratory functions during early childhood:implications for development of asthma prevention strategies.J Allergy Clin Immunol 2005;116:16-24.

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van Rossum AM, Lysenko ES, Weiser JN. Host and bacterialfactors contributing to the clearance of colonization by Strepto-coccus pneumoniae in a murine model. Infect Immun 2005;73:7718-26.

Eder W, Klimecki W, Yu L, et al. Toll-like receptor 2 as a majorgene for asthma in children of European farmers. J Allergy ClinImmunol 2004;113:482-8.

Johnston SL. Innate immunity in the pathogenesis of virus-induced asthma exacerbations. Proc Am Thorac Soc 2007;4:267-70.

Celedn JC, Fuhlbrigge A, Rifas-Shiman S, Weiss ST, Finkel-stein JA. Antibiotic use in the first year of life and asthma inearly childhood. Clin Exp Allergy 2004;34:1011-6.Copyright 2007 Massachusetts Medical Society.

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Breast-Cancer Therapy Looking Back to the FutureAnne Moore, M.D.

Adjuvant therapy for breast cancer treatmentafter surgical removal of the tumor is a majortherapeutic advance that has had a considerable

effect on prolonging disease-free and overall sur-vival. Not all patients benefit from adjuvant ther-apy, however, and certain types of adjuvant therapyare not appropriate for some patients. For exam-ple, adjuvant treatment with tamoxifen, a selec-tive estrogen-receptor modulator, has improved the15-year survival rate among women with estrogen-receptorpositive breast cancer by 31%, but it doesnot benefit women with estrogen-receptornega-tive disease.1 Trastuzumab, a monoclonal anti-body against the human epidermal growth factorreceptor type 2 (HER2), is associated with an im-provement of approximately 50% in disease-freesurvival among the 15 to 20% of women withHER2-positive disease.2,3

In addition to these targeted approaches, adju-vant chemotherapy that includes alkylating agents,antimetabolites, anthracyclines, and taxanes invarious combinations has contributed to the over-all improvement in outcomes among women withoperable breast cancer. As compared with womenwith estrogen-receptorpositive disease, womenwith estrogen-receptornegative breast cancer ben-

efit more from chemotherapy. A recent retrospec-tive analysis of three trials by the Cancer andLeukemia Group B (CALGB) suggests very littleoverall benef it of adjuvant chemotherapy for wom-en with estrogen-receptorpositive breast cancerwho received tamoxifen for 5 years after receivingchemotherapy.4

Is it possible to define an optimal adjuvantchemotherapy program for individual patientswith either estrogen-receptorpositive or estro-

gen-receptornegative breast cancer to maximizethe benefit and minimize toxic effects? The arti-cle by Hayes et al.5 in this issue of the Journal

addresses this question.Hayes et al. report their retrospective analysis

of an adjuvant-chemotherapy trial, CALGB 9344/INT0148 (referred to below as CALGB 9344), forwomen with lymph nodepositive breast cancer.6The trial began in 1994 to test the benefit of add-ing four cycles of the taxane paclitaxel after fourcycles of doxorubicin plus cyclophosphamide. Thetrial also investigated whether doxorubicin athigher than standard doses was beneficial, andthe answer was that escalating the dose of doxo-rubicin did not benefit any subgroup of patients.Women with estrogen-receptorpositive breastcancer received tamoxifen for 5 years after che-motherapy. When the results of the trial werefirst presented at the American Society of ClinicalOncology meeting in May 1998, a small but sta-tistically signif icant benefit from the addition offour cycles of paclitaxel every 3 weeks after doxo-rubicin plus cyclophosphamide was reported.7This result changed clinical practice, and the useof adjuvant paclitaxel rose dramatically well be-fore the publication of the results in 2003.

The study by Hayes et al.5

was designed todetermine whether paclitaxel administered afterdoxorubicin plus cyclophosphamide was equallybeneficial to all subgroups of women enrolled inthe CALGB 9344 trial. New information was add-ed by testing the t issue blocks from the originaltumors for HER2 positivity with the use of assaysfor overexpression and gene amplification. Theresults are noteworthy. There was a significantclinical benefit from the addition of paclitaxel

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Th e n e w e n g l a n d j o u r n a l o f me dicine

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to the treatment of women with HER2-positivebreast cancer. Most of these women had HER2-positive, estrogen-receptornegative breast can-cer, a profile associated with a relatively poorprognosis, but the small subgroup of womenwith HER2-positive, estrogen-receptorpositivedisease also benefited from paclitaxel. However,

women with HER2-negative, estrogen-receptorpositive breast cancer, the most common cate-gory of the disease, did not benefit from theaddition of paclitaxel to doxorubicin plus cyclo-phosphamide.

Why should we spare our patients from pacli-taxel? The toxicity profile of this drug is unique.Hypersensitivity reactions (including, rarely, ana-phylaxis) occur during the infusion of paclitaxel,despite premedication with corticosteroids. Suchreactions were reported in 6% of patients in theCALGB 9344 trial. A transient symptom complex

of myalgia, arthralgia, and neuralgia is commonwithin 2 to 3 days after the infusion. Neurotoxic-ity, the predominant side effect, was reportedin 18% of patients in the CALGB 9344 trial. Forsome patients, numbness and tingling in thehands and feet last for months or even years aftertreatment is completed.8

Thirteen years have passed since the first pa-tient was enrolled in the CALGB 9344 trial. Dur-ing this time, important changes in practice mayhave diminished the value of adding paclitaxel tochemotherapy for women with HER2-negative,estrogen-receptorpositive breast cancer. For in-stance, advances in adjuvant endocrine therapyreduce the proportional benefit of adjuvant che-motherapy for women with estrogen-receptorpositive breast cancer. In postmenopausal women,the incorporation of an aromatase inhibitor (anas-trozole, exemestane, or letrozole) into adjuvanttherapy prolongs disease-free survival more thandoes treatment with tamoxifen for 5 years.9

Hayes and his coauthors caution us not tochange clinical practice on the basis of their retro-

spective analysis, but oncologists have a responsi-bility to their patients to be aware of this report.A similar trial of doxorubicin plus cyclophospha-mide followed by paclitaxel involving 3100 pa-tients was published by the National SurgicalAdjuvant Breast and Bowel Project in 2005. Theresults showed a small benefit in 5-year disease-free survival but no difference in overall survivalas a result of the addition of paclitaxel in women

with estrogen-receptornegative or estrogen-recep-torpositive disease. There was no analysis ofoutcome according to HER2 status.10

In the analysis by Hayes et al., women withHER2-positive breast cancer benefited from receiv-ing four cycles of paclitaxel every 3 weeks afterreceiving doxorubicin plus cyclophosphamide, re-

gardless of the estrogen-receptor status of thetumor. How does this treatment fit into contem-porary adjuvant-chemotherapy programs that in-corporate trastuzumab into the treatment ofHER2-positive breast cancer? Most such programsinclude a taxane. However, in a pivotal trial thatshowed clinically significant improvement in dis-ease-free survival from administration of trastu-zumab after adjuvant chemotherapy, 74% of thepatients were treated without a taxane and stillbenefited from trastuzumab.3

More difficult to define is the effect of the re-

port by Hayes and colleagues on the treatment ofwomen with HER2-negative, estrogen-receptorpositive breast cancer. According to this report,the addition of four cycles of paclitaxel every3 weeks after treatment with doxorubicin plus cy-clophosphamide is unlikely to benefit these pa-tients. However, this is not a call to abandontaxanes for this group of patients. The 3-weekschedule of treatment with paclitaxel is not theonly way to include a taxane in adjuvant therapy.In more recent trials, dose-dense therapy usingthe same doses of doxorubicin plus cyclophospha-mide and paclitaxel every 2 weeks has been shownto be more effective than the same regimen every3 weeks.11 Adjuvant trials that use paclitaxel week-ly instead of every 3 weeks and the adoption of thealternative taxane, docetaxel, for adjuvant therapypoint to more choices.12,13 It would be of greatvalue if the investigators in charge of these morerecent trials analyzed their results retrospectivelywith respect to HER2 and estrogen-receptor status.

Leaders of clinical trials should continue tolook backward, when appropriate, for data such

as those presented by Hayes et al. In looking tothe future, correlative science must be incorporat-ed into modern clinical trials in breast cancer.The days of one size fits all therapy for patientswith breast cancer are coming to an end.

No potential conflict of interest relevant to this article wasreported.

From the Division of HematologyOncology, Weill CornellMedical College, Cornell University Medical Center, New York.



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Early Breast Cancer Trialists Collaborative Group (EBCTCG).Effects of chemotherapy and hormonal therapy for early breastcancer on recurrence and 15-year survival. Lancet 2005;365:1687-717.

Romond EH, Perez EA, Bryant J, et al. Trastuzumab plusadjuvant chemotherapy for operable HER2-positive breast cancer.N Engl J Med 2005;353:1673-84.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastu-zumab after adjuvant chemotherapy in HER2-positive breast

cancer. N Engl J Med 2005;353:1659-72.Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-recep-tor status and outcomes of modern chemotherapy for patientswith node-positive breast cancer. JAMA 2006;295:1658-67. [Erra-tum, JAMA 2006;295:2356.]

Hayes DF, Thor AD, Dressler LG, et al. HER2 and response topaclitaxel in node-positive breast cancer. N Engl J Med 2007;357:1496-506.

Henderson IC, Berry DA, Demetri GD, et al. Improved out-comes from adding sequential paclitaxel but not from escalatingdoxorubicin dose in an adjuvant chemotherapy regimen for pa-tients with node-positive primary breast cancer. J Clin Oncol2003;21:976-83.

Henderson IC, Berry D, Demetri GD, et al. Improved disease-free (DFS) and overall survival (OS) from the addition of sequen-tial pacl itaxel (T) but not from the escalation of doxorubicin (A)

dose level in the adjuvant chemotherapy of patients (pts) with

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node-positive primary breast cancer (BC). Proc Am Soc Clin On-col 1998;17:101a. abstract.

Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral neu-ropathy: pathogenesis and emerging therapies. Support CareCancer 2004;12:619-25.

Lin NU, Winer EP. Optimal use of aromatase inhibitors: to leador to follow? J Clin Oncol 2007;25:2639-41.

Mamounas EP, Bryant J, Lembersky B, et al. Paclitaxel afterdoxorubicin plus cyclophosphamide as adjuvant chemotherapy

for node-positive breast cancer: results from NSABP B-28. J ClinOncol 2005;23:3686-96.Citron ML, Berry DA, Cirrincione C, et al. Randomized tria l

of dose-dense versus conventionally scheduled and sequentialversus concurrent combination chemotherapy as postoperativeadjuvant treatment of node-positive primary breast cancer: firstreport of Intergroup Trial C9741/Cancer and Leukemia Group BTrial 9741. J Clin Oncol 2003;21:1431-9. [Erratum, J Clin Oncol2003;21:2226.]

Sparano JA, Wang M, Martino S, et al. Phase III study ofdoxorubicin-cyclophosphamide followed by paclitaxel or docetaxelgiven every 3 weeks or weekly in operable breast cancer: resultsof Intergroup Trial E1199. J Clin Oncol 2007;25:Suppl:516. ab-stract.

Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxelfor node-positive breast cancer. N Engl J Med 2005;352:2302-13.

Copyright 2007 Massachusetts Medical Societ y.

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The Quality of Childrens Health Care Matters Time to Pay Attention

James M. Perrin, M.D., and Charles J. Homer, M.D., M.P.H.

High-quality health care matters for all children and is critically important for some. In manyways, health care for children serves the samefunction as health care for adults. For example,the incidence of chronic illness in children is in-creasing, resulting in a substantial illness burdenwith a substantial cost.1 How well chronic con-ditions are managed profoundly influences bothshort-term and long-term outcomes, not only forcommon diseases such as asthma but also forrarer conditions such as cancer, cystic fibrosis,and sickle cell disease.2

Many aspects of childrens health care have noparallel in adult health services.3 The dispropor-tionate rates of poverty among children and ado-

lescents mean that childrens health services mustaddress health needs despite limited resources.Because children are dependent on caregivers andcommunity resources, providers of child healthcare must enhance the competency of these care-givers and coordinate a broad array of commu-nity services. Childrens health care settings typ-ically involve developmental surveillance; theidentification of sensory, learning, and behavior-al disorders; and monitoring for family violence

and child abuse. Optimally, such programs pro-vide evidence-informed counseling that promotespositive behaviors related to individual health,family functioning, and psychological and devel-opmental well-being all of which are beyondtraditional health care services with effectsthat last for the rest of a childs life.

The article by Mangione-Smith et al.4 in thisissue of theJournal, although addressing tradition-al health care services and ambulatory care only,nonetheless presents sobering findings. The au-thors examined hundreds of indicators of quality,developed according to complex but well-estab-lished methods from RAND and UCLA, empha-sizing the most common reasons for which

children use the health care system. They inten-tionally studied a full spectrum of ambulatoryservices at least within the traditional healthcare domains of preventive care, care for acuteconditions, and care for chronic conditions for children of all ages.

Their observations are shocking: the right ser-vices appear to be carried out less than half thetime. Services are not delivered when they shouldbe, or they are delivered when they should not


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